The long-term objective of this proposal is to supply information which will aid in the identification of conditions under which individuals might be susceptible to organothiophosphate pesticide- induced toxicity. It seeks to accomplish this objective by determining the relative roles of hepatic and extrahepatic biotransformation of these chemicals in mediating their acute toxcicities. Implicit in this approach is the evaluation of numerous factors which affect these critical metabolic pathways. It is expected that these studies will provide information useful in assessing the health hazards of organothiophosphate insecticides, as well as their potential for toxic interactions with certain other zenobiotics. Furthermore these studies will contribute to the fundamental knowledge of those metabolic systems involved in the biotransformation of organothiophosophate insecticides. The specific aims to be addressed in this research are as follows: 1. To further investigate whether the toxic oxygen analogs produced intrahepatically from organothiophosphate pesticides enter the general circulation, or whether they undergo extensive intrahepatic detoxification thereby preventing their escape from the liver. 2. To determine if the A-esterase in blood has the capacity to prevent the passage of those oxons escaping liver to target tissues such as brains and lungs. 3. To investigate the toxicological significance to extrahepatic activation of certain organothiophosphate insecticides. 4. To identify and characterize the metabolic activation and detoxification of organothiophosphate insecticides by human placenta. 5. To evaluate the role of gluthathione-mediated biotransformation of dimethyl-substituted organothiophosphates in vivo in the detoxification of these pesticides.